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High Stakes for Gene Therapy

After a decade of disappointment and a teenager’s death, this experimental treatment faces a crucial test. Can it cure hemophilia?
March 1, 2000

Kathy High doesn’t sleep well these days. A chronic insomniac, the University of Pennsylvania hematologist now gets even less rest than usual. The reason? Stress. High does gene therapy.

These are not easy times for High and other researchers trying to cure patients with DNA. A few hundred yards down the road from High’s Children’s Hospital of Philadelphia office, over in Penn’s main hospital, 18-year-old Jesse Gelsinger died last September after receiving gene therapy for a rare liver disorder. The teenager’s death prompted highly public soul-searching by the gene-therapy community and intense scrutiny by the Food and Drug Administration. In January, the FDA put all of the human trials run out of Penn’s Institute for Human Gene Therapy, including the one Gelsinger had volunteered for, on indefinite hold.

More quietly, and beginning even before Gelsinger’s death, once-enthusiastic private companies have been backing off from gene therapy. Swiss drug firm Novartis pulled the plug on its flagship gene-therapy project, for brain tumors, in 1998. Biotech powerhouse Chiron virtually eliminated new in-house gene-therapy research last year. Of 14 biotech firms sponsoring gene-therapy trials in 1995, half no longer exist as independent companies, and the stock prices of most of the survivors have languished.

Driven by the logic of the bottom line, many companies have decided it’s more sensible to invest in proven drug strategies than in a highly experimental treatment that has so far yielded no definitive cures. At a conference last November, the Salk Institute’s Inder Verma-a prominent researcher in the field-characterized gene therapy’s successes to date as “almost nonexistent.” But Verma, High and many of their colleagues have chosen to persevere despite public scrutiny and industry’s chilly feet. One motivation: They are working on genetic treatments for hemophilia and they believe that this disease may well be the first to be cured by gene therapy.

For the field of gene therapy, there’s a lot riding on the outcome of the hemophilia research. If there is a cure, the bloom-and the corporate investments-might come back. If it’s a bust, the entire enterprise moves one step closer to a dead end. Speaking to a small group of fatigued colleagues during the annual American Society for Gene Therapy meeting last June, then-president Jim Wilson, director of Penn’s Institute for Human Gene Therapy, captured the mood of the moment. “The stakes are incredibly high,” Wilson said. “For once I may say what I really think: I hope to God this works.”


Kathy High’s father once thought she’d make a better scientist than doctor, she says, “because it was his impression that I panicked in the face of danger.” That’s an overstatement, High claims, and even as her colleagues down the street face an FDA-imposed shut-down, still in effect as TR went to press, she isn’t beating a retreat. She has a couple of reasons to stand her ground. For one thing, she is using a safer gene-therapy delivery system, or “vector,” than the one that killed Gelsinger. And the disease she’s trying to cure-hemophilia-is more common and less complicated to treat genetically than Gelsinger’s.

High works in partnership with Alameda, Calif.-based Avigen and Stanford geneticist Mark Kay, and they have plenty of competition. Two other biotech firms, Transkaryotic Therapies (TKT) of Cambridge, Mass., and Emeryville, Calif.’s Chiron, have also launched clinical trials to test their own versions of hemophilia gene therapy. At least four other biotech companies have shown interest in joining the race.

Gene therapists are looking to hemophilia as the disease whose cure will begin to justify the billions lavished on research, attract new private investment, fulfill the hype and dispel the stigma of failure. “That kind of success will have a big impact,” says Joe Glorioso, director of the University of Pittsburgh’s gene-therapy center, “at least in the investment community, on whether we should support this kind of biotechnology or not.” Beyond redeeming the field, a cure for hemophilia would be a late but just reward for a patient population that has suffered great pain over the last 20 years.

Hemophilia is an inherited bleeding disorder that afflicts males almost exclusively. It’s caused when the gene for either of two protein “clotting factors,” factor VIII or factor IX, is damaged or missing. Most people with hemophilia-about 17,000 in the United States alone-treat their bleeds by injecting concentrated “factor” made from blood products or by genetic engineering. During the early 1980s, blood products contaminated with HIV decimated the hemophilia community. “Sixty percent of our families have had somebody die or have AIDS from transfused material,” says New York’s Mt. Sinai Medical Center hemophilia specialist Lou Aledort.

John Lanzon, a 52-year-old medical technologist in Detroit, is typical of his generation of hemophilia sufferers. Lanzon walks with a limp, the legacy of dual knee-replacement surgery, and his elbows resemble gnarled driftwood. That’s because people with hemophilia do not bleed uncontrollably from cuts but instead tend to bleed into their joints, which suffer long-term damage, partly from enzymes that break down the blood. Contaminated factor gave Lanzon hepatitis B and C, as well as HIV, though he has yet to develop AIDS. Better blood-screening and heat-treatment practices, along with genetic engineering, have made today’s treatments safe, but hardly ideal. “Factor will stop the bleeding,” Lanzon says, “but it’s not going to do a thing for the inflammation and the pain.”

Because clotting factors are tremendously expensive (more than $1,000 a dose), most people with hemophilia, including Lanzon, treat themselves only after a bleed starts. Preventive treatments are a painful burden for children. Adding a good copy of the defective gene, if it works, would put a constant stream of clotting factor into the blood and eliminate bleeds altogether. Rather than just serving as a palliative, it would be a cure. “A single treatment that would keep the boys from having pain or permanent joint disability,” says Children’s Hospital of Philadelphia hematologist Katie Manno, the doctor in charge of administering High’s experimental treatment to patients, “would be perfect.”

An Unlikely Crusader

At first glance, High seems an unlikely person to bear the hopes of patients and researchers for a hemophilia cure. She’s a small, tidily dressed woman whose disarming friendliness and pleasant North Carolina diction make her easy to underestimate. There’s not a trace of condescension in her voice-something rare in a doctor of her stature. But she’s a woman of force who has made her share of enemies among colleagues and competitors. “She’s straight, she says what she believes, and people don’t want to hear the truth,” says Lou Aledort.

High has relentlessly pursued gene therapy for hemophilia for more than a decade. In the late 1980s, when she was a junior faculty member at the University of North Carolina, her lab cloned the canine factor IX gene. After she left UNC, High continued experiments with the university’s colony of hemophilic dogs. Her team’s successful treatment of the dogs is one reason researchers think hemophilia gene therapy might well work in humans.

Another reason is that the new clotting factor gene would only have to find its way into a relatively small number of cells to make a difference for patients. Just 1.5 percent of the normal level of factor should greatly shorten bleeding episodes, and 5 percent should effectively cure. What’s more, the protein only has to make it into the bloodstream, not a particular organ or tissue, to do its job.

Finally, knowing if the treatment is working-or not-won’t be hard. Just take a blood sample, separate plasma from red cells, and run a simple clotting test. A big problem with other diseases that researchers have tried to treat with gene therapy, such as cystic fibrosis, is that it’s almost impossible to measure accurately levels of normal protein, and improvements in symptoms might not be obvious for years. In this respect, hemophilia is easy, says High: “All we’ve got to do is draw blood.”

Still, such a clear “readout” means failure will be obvious right along with success. And that’s just one of the things that keeps High up at night. She frets, for example, over premature data leaks, and worries that reporters will get their facts wrong. She also wonders whether she should be spending more time with her three children. But as she watched a surgeon inject the first dose of her vector into a patient’s thigh last June, her anxiety gave way (at least temporarily) to relief: Nothing bad happened.

Safe and Sound?

All three of the human hemophilia trials under way-involving 21 patients as TR went to press-are primarily safety trials. But intense pressure to show that gene therapy is working has prompted the companies involved to spin the best possible story. Last June, Chiron allowed The Washington Post to interview a patient, who told the reporter that a nosebleed ended sooner than usual. The TKT trial’s principal investigator, Harvard hematologist David Roth, told TR that not only had none of his patients suffered significant side effects, but that “in at least one case, there appears to be a decrease in spontaneous bleeding.” Still, Roth stressed that it was too early to draw conclusions.

Avigen made the biggest splash. A December press release announced that the first three patients had “factor IX activity” and needed fewer injectable doses of factor than they had before the trial. Mt. Sinai Medical Center’s Aledort saw the data in early December. Though guardedly enthusiastic, he found the results to be far from conclusive. “I think it’s much too early to say this is the answer,” he says. One patient, for example, had indeed generated a “therapeutic” level of factor IX-but that level subsequently dropped. As for patients needing less factor after the treatment, “the question is, is this a placebo effect, or is it real?” says Aledort. “How the hell does anybody know that yet?” The jury will be out for a while. “If you really went a year, even six months, with consistent levels [of factor], I would say it’s working,” says Aledort.

And even though there weren’t obvious ill effects in the first six months of treatment, that doesn’t mean there won’t ever be any. One of the biggest dangers is that of inhibitory antibodies, or “inhibitors.” The very word fills hemophilia sufferers with dread. Overall, about 20 percent will, at some point, develop inhibitors that prevent factor from working. Massive doses of factor can often overcome these antibodies, but people with inhibitors tend to suffer more and die earlier than those without. Because of the hemorrhage risk, “surgery becomes impossible,” says Aledort, and “trauma leads to death not infrequently.”

Cure or Catastrophe?

By mid-summer, High’s trial and the Chiron trial should be complete. (TKT plans to finish by the end of the year.) Results are keenly awaited. As Jim Wilson told hemophilia researchers at the June American Society for Gene Therapy meeting: “The world is watching what you guys are doing, and what’s happening in the clinical trials.”

A cure for hemophilia could galvanize gene therapy. “It would be a tremendous boost to the field, particularly in view of the negative events that have happened recently,” says University of Michigan researcher Jeff Chamberlain, who’s working on Duchenne muscular dystrophy. Not only would the achievement bolster morale, Chamberlain says, it could also attract bright researchers to the field and help promote the technology across the whole spectrum of diseases. Industry analysts agree. “This would be one of the first steps towards validating gene therapy as a treatment protocol,” says Anthony Shimkin of Wedbush Morgan Securities in Los Angeles. But the flip side of the scenario is that failure in hemophilia-given all the disease’s advantages-could shake confidence in gene therapy even further. “It would be a huge problem,” says biotech analyst Al Rauch of First Union Securities in Chicago, “because you can’t really think of a good reason it wouldn’t work.” Disappointment in hemophilia, Rauch says, “would indicate people have very little understanding of how [gene therapy] works.”

Might that stall the entire field? “I think it’s a possibility,” says Shimkin. But he’s quick to stress that gene therapy will survive regardless of the outcome of the hemophilia trials: “It won’t be so much a case of, ‘gene therapy’s not here to stay,’ as ‘let’s go back to the drawing board.’”

Gene therapy’s success or failure in hemophilia could be known in a few months, but some questions won’t be answered for years. Will the new gene, randomly lodged in a cell’s chromosome, trigger cancer? Will it make its way into germ cells (sperm, in this case) and get passed on to children? That could be catastrophic, since every cell in the body would inherit the foreign gene. Normally, cells selectively repress the expression of many genes, keeping them dormant, but the new gene, because of the way it’s engineered, would be turned on everywhere. Such hyperactivity could be “devastating” to a developing fetus, says gene-therapy researcher Jon Gordon of Mt. Sinai Medical Center.

Most researchers working with viral vectors consider these risks minimal. (High’s lab found that Avigen’s vector makes it into the testes of rabbits, but not their sperm.) Still, Jesse Gelsinger’s shocking death showed how a vector commonly considered safe could deliver an ugly surprise. “We are not very sophisticated, yet, in really controlling what we’re doing when we give these vectors,” says Gordon. “Their biological distribution, their fate, and how they behave in vivo-we have a lot of knowledge that’s yet to be acquired there.”

By the end of the year, when the last of these trials should wrap up, over 30 hemophilic patients will have exposed themselves to largely unknown risks. “They’re really pretty brave,” says Kathy High. Safety aside, will gene therapy work? High is confident hers will, especially at the higher doses planned for the end of the trial. But what if inhibitors develop-or worse? “If there was a death in a hemophiliac, that would set the field back a decade,” says University of North Carolina hematologist Gilbert White.

High, as always, remains alert for any sign of trouble-even in the fortune cookies that come with the Chinese dinners she likes to order. A recent one seemed ominous: “When things are going well is the time to prepare for danger.”

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